Processes for preparing cyclopentenones and cyclopentenones for the synthesis of benzindene prostaglandins

Abstract

The present invention provides novel processes of preparing racemic and optically active cyclopentenones of Formula I: The invention also provides novel cyclopentenones of formula I in racemic or optically active form.

1. A process for preparing a racemic cyclopentenone of Formula I 
       
         
           
           
               
               
           
         
         wherein P 1  a protecting group for the phenol group, 
         comprising the steps of: 
         (a) reacting furan with an acyl donor of the acid compound of Formula V 
       
       
         
           
           
               
               
           
         
         to form a 2-acylfuran of Formula IV 
       
       
         
           
           
               
               
           
         
         (b) reacting the 2-acylfuran of Formula IV with a reducing agent to form the corresponding furancarbinol compound of formula III: 
       
       
         
           
           
               
               
           
         
         and 
         (c) subjecting the furancarbinol compound of formula III to a rearrangement and isomerization to form the racemic compound of Formula I. 
       
     
     
       2. The process according to  claim 1 , wherein P 1  is a C 1-8  alkyl, allyl, unsubstituted or substituted benzyl, acetyl, C 1-8  alkylcarbonyl, methoxymethyl, methoxythiomethyl, 2-methoxyethoxymethyl, bis(2-chloroethoxy)methyl, tetrahydropyranyl, tetrahydrothiopyranyl, 4-methoxytetrahydropyranyl, 4-methoxytetrahydrothiopyranyl, tetrahydrofuranyl, tetrahydrothiofuranyl, 1-ethoxyethyl, 1-methyl-1-methoxyethyl, triphenylmethyl, and SiR a R b R c  wherein R a , R b  and R c  are each independently a C 1-8  alkyl, phenyl, benzyl, a substituted phenyl, or a substituted benzyl. 
     
     
       3. The process according to  claim 2 , wherein P 1  is a C 1-8  alkyl, allyl, or an unsubstituted or substituted benzyl. 
     
     
       4. The process according to  claim 1 , wherein the acyl donor is selected from the group consisting of chloroacetic anhydride or trifluoroacetic anhydride or a mixture thereof. 
     
     
       5. The process according to  claim 1 , wherein the reducing agent is selected from the group consisting of NaBH 4 , LiBH 4 , LiAlH 4 , or (iso-Bu) 2 AlH or a mixture thereof. 
     
     
       6. A process for preparing a compound of Formula I enriched in the (R)-enantiomer and having an optical purity of at least 95% enantiomeric excess, 
       
         
           
           
               
               
           
         
         wherein P 1  is as defined in  claim 1 , comprising the steps of: 
         (e) enantioselectively (R)-esterifying the racemic alcohol mixture of the compound of Formula I with an acyl donor of Formula D 
       
       
         
           
           
               
               
           
         
         wherein R 1  and R 2  are independently a C 1-6  alkyl or H, and a first lipase; 
         (f) removing the unreacted (S)-alcohol; and 
         (g) deacylating the resultant (R)-ester. 
       
     
     
       7. The process according to  claim 6 , wherein the acyl donor of Formula D is vinyl acetate, isopropenyl acetate, vinyl valerate, isopropenyl valerate, vinyl butyrate, or isopropenyl butyrate or a mixture thereof. 
     
     
       8. The process according to  claim 6 , wherein the first lipase is derived from  Candida antarcitica, Achromobacter  spp.,  Alcaligenese  spp.,  Pseudomonas fluorescens, Pseudomonas stutzri , or  Pseudomonas cepacia.    
     
     
       9. The process according to  claim 6 , wherein the deacylation step (g) comprises an enzymatic cleavage reaction using a second lipase derived from  Candida antarcitica, Psudomonas  spp. or  Achromobacter  spp or a mixture thereof. 
     
     
       10. The process according to  claim 9 , wherein the second lipase is derived from  Candida antarcitica.    
     
     
       11. The process according to  claim 6 , wherein the deacylation step (g) is a chemical hydrolysis. 
     
     
       12. The process according to  claim 6 , wherein step (t) comprises converting the unreacted (S)-alcohol into a corresponding (R)-ester by reacting the (S)-alcohol with an acyloxy donor of Formula R 3 COOH, wherein R 3  is as defined in  claim 5  for R 1  in the presence of a dialkylazodicarboxylate and a triarylphosphine. 
     
     
       13. The process according to  claim 12 , wherein the dialkylazodicarboxylate is diethylazodicarboxylate, diisopropylazodicarboxylate, or dibenzylazodicarboxylate or a mixture thereof. 
     
     
       14. The process according to  claim 12 , wherein the triarylphosphine is triphenylphosphine. 
     
     
       15. A racemic or an optically active compound of Formula I: 
       
         
           
           
               
               
           
         
         wherein P 1  is a protecting group for the phenol selected from the group consisting of a C 1-8  alkyl, allyl, unsubstituted or substituted benzyl, acetyl, C 1-8  alkylcarbonyl, methoxymethyl, methoxythiomethyl, 2-methoxyethoxymethyl, bis(2-chloroethoxy)methyl, tetrahydropyranyl, tetrahydrothiopyranyl, 4-methoxytetrahydropyranyl, 4-methoxytetrahydrothiopyranyl, tetrahydrofuranyl, tetrahydrothiofuranyl, 1-ethoxyethyl, 1-methyl-1-methoxyethyl, triphenylmethyl, and SiRR a R b R c  wherein R a , R b  and R c  are each independently a C 1-8  alkyl, phenyl, benzyl, a substituted phenyl, or a substituted benzyl. 
       
     
     
       16. A compound according to  claim 15 , wherein P 1  is benzyl or a substituted benzyl. 
     
     
       17. A compound according to  claim 15 , wherein P 1  is SiR a R b R c  wherein R a , R b  and R c  are each independently a C 1-8  alkyl, phenyl, benzyl, a substituted phenyl, or a substituted benzyl. 
     
     
       18. A compound according to  claim 17 , wherein R a , R b  and R c  are each independently a C 1-8  alkyl. 
     
     
       19. A compound according to  claim 15 , wherein P 1  is a C 1-8  alkyl. 
     
     
       20. A compound according to  claim 15 , wherein P 1  is acetyl or a C 1-8  alkylcarbonyl. 
     
     
       21. A compound according to  claim 15  enriched in the (R)-enantiomer and having an optical purity of at least 95% enantiomeric excess. 
     
     
       22. A compound according to  claim 15  enriched in the (R)-enantiomer and having an optical purity of at least 99% enantiomeric excess. 
     
     
       23. A compound according to  claim 15  enriched in the (R)-enantiomer and having an optical purity of at least 99.9% enantiomeric excess.